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1477 First efficacy and multi-omic analysis data from phase 1 clinical trial of oncolytic viral immunotherapy with CAN-2409 + valacyclovir in combination with nivolumab and standard of care in newly diagnosed high-grade glioma
  1. Patrick Wen1,
  2. Caroline Duault2,
  3. Edgar Gonzalez-Kozlova2,
  4. Kevin Brennan2,
  5. Tyson Holmes2,
  6. Seunghee Kim-Schulze2,
  7. Kai Nie2,
  8. Kimberly Argueta2,
  9. Jacques Fehr2,
  10. Mina Pichavant2,
  11. Diane Del Valle2,
  12. Andrew Gentles2,
  13. Sacha Gnjatic2,
  14. Holden Maecker2,
  15. Xiaobu Ye3,
  16. David Reardon1,
  17. Wenya Linda Bi1,
  18. Pierpaolo Peruzzi1,
  19. Nirav Patel1,
  20. Roy Strowd4,
  21. Stephen Tatter4,
  22. Ian Lee5,
  23. Tobias Walbert5,
  24. James Snyder5,
  25. Steven Brem6,
  26. Arati Desai6,
  27. Stephen Bagley6,
  28. Nduka Amankulor7,
  29. Frank Lieberman7,
  30. Megan Mantica7,
  31. Lenika Lopez8,
  32. Susan Bell8,
  33. Andrea Manzanera8,
  34. Sean Lawler1,
  35. Lixian Jin9,
  36. Neeraja Danda3,
  37. Serena Desideri10,
  38. L Burt Nabors11,
  39. Stuart Grossman10,
  40. E Chiocca1,
  41. Paul Tak8 and
  42. Francesca Barone8
  1. 1Dana-Farber Cancer Institute, Boston, MA, USA
  2. 2CIMAC Consortium, Stanford, CA, USA
  3. 3Adult Brain Tumor Consortium, Baltimore, MD, USA
  4. 4Wake Forest Baptist Health, Winston-Salem, NC, USA
  5. 5Henry Ford Health, Detroit, MI, USA
  6. 6University of Pennsylvania Hospital, Philadelphia, PA, USA
  7. 7University of Pittsburgh Medicine, Pittsburgh, PA, USA
  8. 8Candel Therapeutics, Nedeham, MA, USA
  9. 9Bristol-Meyers Squibb, Lawrenceville, NY, USA
  10. 10Adult Tumor Brain Consortium, Baltimore, MD, USA
  11. 11University of Alabama, Birmingham, AL, USA


Background High-grade glioma (HGG) is characterized by a highly immunosuppressive tumor microenvironment and poor prognosis. Limited advances have been made in HGG standard of care (SoC) treatment, with immunotherapy failures reported in this indication. CAN-2409 is a replication-defective adenovirus that delivers HSV thymidine kinase to cancer cells, resulting in local conversion of oral valacyclovir into a toxic metabolite inducing immunogenic cell death. Preclinical data in a mouse model of HGG suggest CAN-2409 potential synergy with anti-PD1 agents.1 An ongoing phase 1 clinical trial is evaluating safety, initial efficacy and immunological biomarkers associated with the combination of CAN-2409/valacyclovir with nivolumab plus SoC in patients with newly diagnosed HGG.

Methods Forty-one patients with HGG were recruited from February 2019 to March 2021. CAN-2409 was injected into the resection bed during neurosurgery, followed by valacyclovir and SoC chemoradiation. Nivolumab was initiated on day 15 and administered every 2 weeks for up to 52 weeks. Tumor and peripheral blood samples were longitudinally collected (figure 1) from 35 patients (evaluable population). Immune profiling was performed by the CIMAC network including plasma proteomics, multidimensional flow cytometry by CyTOF, whole exome sequencing (WES), TCR analysis and RNA sequencing.

Results Median OS (mOS) for patients with methylated MGMT promoter was 30.6mo for patients undergoing gross total resection (GTR) and 12.6mo for patients undergoing sub-total resection (STR). mOS for patients with unmethylated MGMT was 13.2mo (GTR) and 15.9mo (STR). Propensity score matching analysis is ongoing to evaluate mOS, controlling for known prognostic factors. Plasma proteomics at 3-week post-treatment identified increases in CXCL9, CCL11, GZMA, IFNG, CCL19, MCP1, and MCP3 concentrations (LogFC>1, FDR<0.05). Nivolumab treatment associated with significant increases in CXCL9, IL10, and PDCD1 concentrations (LogFC>1, FDR<0.05) and a trend towards elevated LAMP3, CXCL13, CXCL1, and TNFRSF9 concentrations (logFC>0.5, FDR<0.05 at week 5). Patients with methylated MGMT promoter displayed (at weeks 5 and 11) a significant increase in IL-5, IL-7, IL-10, CD4, CD27, CD40, CD38, CFS-1 and ICOSLG concentrations (FDR<0.05). Baseline concentrations of TIE2 correlated with survival (FDR<0.05). CyTOF analysis unveiled significant post-treatment changes, including increase in activated CD4 (p 0.0011; week 5), CD8 (p 0.0189; week 5), CD69+ gamma delta T cells (p0.0324; week 5), and plasmacytoid dendritic cells (p=0.0327, p=0.0020 at week 5 and 11). Additional biomarker analysis and canonical correlation analysis with clinical responses are ongoing.

Abstract 1477 Figure 1

Schema of treatment and biomarker timepoints

Conclusions Combination treatment of CAN-2409/valacyclovir plus nivolumab and SoC induces profound immunological changes and appears to associate with encouraging survival data.

Acknowledgements We would like to thank the Adult Brain Tumor Consortium for oversight on the study and the participating patients and their families, as well as site research and clinical staff.

Trial Registration NCT03576612


  1. Speranza MC, Passaro C, Ricklefs F, Kasai K, Klein SR, Nakashima H, Kaufmann JK, Ahmed AK, Nowicki MO, Obi P, Bronisz A, Aguilar-Cordova E, Aguilar LK, Guzik BW, Breakefield X, Weissleder R, Freeman GJ, Reardon DA, Wen PY, Chiocca EA, Lawler SE. Preclinical investigation of combined gene-mediated cytotoxic immunotherapy and immune checkpoint blockade in glioblastoma. Neuro Oncol 2018;20(2):225–235.

Ethics Approval The protocol was reviewed by the FDA and the Institutional Review Boards at participating institutions. All study participants provided written informed consent before enrollment.

Consent All patients provided informed consent for this trial.

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